This thesis describes the synthesis and application of a new series of amphiphilic graft copolymers with a hydrophobic polyolefin backbone and pendent hydrophilic poly(ethylene glycol) (PEG) grafts. These copolymers are synthesized by ruthenium benzylidene-catalyzed ring-opening metathesis polymerization (ROMP) of PEG-functionalized cyclic olefin macromonomers to afford polycyclooctene- graft-PEG (PCOE-g-PEG) copolymers with a number of tunable features, such as PEG graft density and length, crystallinity, and amphiphilicity. Macromonomers of this type were prepared first by coupling chemistry using commercially available PEG monomethyl ether derivatives and a carboxylic acid-functionalized cycloctene. In a second approach, macromonomers possessing a variety of PEG lengths were prepared by anionic polymerization of ethylene oxide initiated by cyclooctene alkoxide. This methodology affords a number of benefits compared to coupling chemistry including an expanded PEG molecular weight range, improved hydrolytic stability of the PEG-polycyclooctene linkage, and a reactive hydroxyl end-group functionality for optional attachment of biomolecules and probes. The amphiphilic nature of these graft copolymers was exploited in oil-water interfacial assembly, and the unsaturation present in the polycyclooctene backbone was utilized in covalent cross-linking reactions to afford hollow polymer capsules. In one approach, a bis-cyclooctene PEG derivative was synthesized and co-assembled with PCOE-g-PEG at the oil-water interface. Upon addition of a ruthenium benzylidene catalyst, a cross-linked polymer shell is formed through ring-opening cross-metathesis between the bis-cyclooctene cross-linker and the residual olefins in the graft copolymer. By incorporating a fluorescent-labeled cyclooctene into the graft copolymer, both oil-water interfacial segregation and effective cross-linking were confirmed using confocal laser scanning microscopy (CLSM). In a second approach, reactive functionality capable of chemical cross-linking was incorporated directly into the polymer backbone by synthesis and copolymerization of phenyl azide and acyl hydrazine-functional cyclooctene derivatives. Upon assembly, these reactive polymers were cross-linked by photolysis (in the phenyl azide case) or by addition of glutaraldehyde (in the acyl hydrazine case) to form mechanically robust polymer capsules with tunable degradability (i.e. non-degradable or pH-dependent degradability). This process permits the preparation of both oil-in-water and water-in-oil capsules, thus enabling the encapsulation of hydrophobic or hydrophilic reagents in the capsule core. Furthermore, the assemblies can be sized from tens of microns to the 150 nm - 1 µm size range by either membrane extrusion or ultrasonication techniques. These novel capsules may be well-suited for a number of controlled release applications, where the transport of encapsulated compounds can be regulated by factors such as cross-link density, hydrolytic stability, and environmental triggers such as changes in pH.

The rise in bacterial resistance and the declining approval rate of novel anti-infective drugs are a major threat to global public health. Antimicrobial peptides (AMPs), found in almost every multicellular organism, have attracted considerable attention as models for the design of new therapeutic agents due to their broad spectrum activity and reduced bacterial resistance development. This dissertation focuses on the development of a new series of synthetic mimics of antimicrobial peptides (SMAMPs) from simple aryl scaffolds using Suzuki Miyaura coupling. This novel design allows easy tuning of the conformation, overall hydrophobicity of the molecule, amphiphilicity, and the number of charges in order to develop a structure-activity relationship. The antimicrobial activities of the SMAMPs against both gram-positive and gram-negative bacteria suggest that improving the selectivity requires fine-tuning of one or more of these parameters, with overall hydrophobicity and charge having a more significant impact than conformational rigidity. Furthermore, comparing the activities of SMAMPS with facially amphiphilic and disrupted amphiphilic topologies confirmed that amphiphilicity is an important design parameter for attaining antimicrobial activity, especially against gram-negative bacteria. This aryl scaffold design has led to the development of several highly active SMAMPs with selectivities >200 against both gram-positive S. aureus and gram-negative E. coli, which is nearly 20 times higher than that of the conventional AMP, MSI-78. One of these SMAMPs also shows a unique immunomodulatory response involving the induction of both cytokines and chemokines, which can have significant therapeutic potential. Similar chemistry was employed in the development of novel lipopeptide mimics (LPMs), where the attachment of pendant aliphatic chains to the tri-aryl backbone structure can be used to modulate the activity. The second project in this dissertation concerns the investigation of the influence of the cobalt density in the phase-separated domains in the ferromagnetic block copolymer materials A series of metal-containing block-random copolymers composed of an alkyl-functionalized homo block (C16 ) and a random block of cobalt complex- (Co) and ferrocene complex-functionalized (Fe) units was synthesized via ring-opening metathesis polymerization (ROMP). Taking advantage of the block-random architecture, the influence of dipolar interactions on the magnetic properties of these nanostructured BCPs was studied by systematically varying the molar ratio of the Co units to the Fe units, while maintaining the cylindrical phase-separated morphology. A decrease in the cobalt density weakens the dipolar interactions between the cobalt nanoparticles, leading to the transition from a room temperature ferromagnetic material to a superparamagnetic material. These results confirm that the dipolar interactions of the cobalt nanoparticles within the phase-separated domains are responsible for the (unexpected) room temperature ferromagnetic properties of the nanostructured BCPs.

Analogous disproportionation processes lead to similarities in the structures present at incipient coacervation to those within the subsequent dense phase. Coacervation in polyelectrolyte/mixed micelle system is induced by temperature to explore structural evolution before, during and after coacervation. Assemblies of polyelectrolyte-micelle primary complexes appear to be governed by the interparticle interaction, a delicate balance between short-range attraction and long-range repulsion. Dilution-induced coacervation in opposite to self-suppression is facilitated by the presence of smaller particles in size but larger in number as a result of the favourable interparticle interaction. While dilution leads to formation of smaller particles that can phase separate easily, larger particles can achieve coacervation by increase in temperature, a greater entropy contribution. Dynamic light scattering reveals a progressive increase in aggregate size with temperature up to the phase transition at Tphi;, followed by splitting of these aggregates into respectively smaller and larger particles. The fact that the process of coacervation itself is accompanied by the expulsion of smaller aggregates to form near-neutral aggregates is known as a type of macroion disproportionation. At incipient coacervation, the transfer among soluble complexes of excess macroions to achieve near-neutrality is found to be analogous to the expulsion (with counterions) of excess macroions into dilute domains in the coacervates. The driving forces of ion-pairing and counterion release, in one-phase and dense phase states, use similar strategies of disproportionation and local charge neutralization to form analogous transient structures. The transient nature of coacervate structure is further investigated by rheology and total internal reflection microscopy in PDADMAC/BSA coacervates. While polyelectrolyte-colloid coacervates exhibit structural rearrangement in the coacervate correlated with the compositional difference between supernatant and coacervate, heteroprotein coacervation appears to have a fixed stoichiometry in both phases. The absence of disproportionation is suggested to be responsible for the highly limited conditions of pH, ionic strength I, total protein concentration Cp, and BLG:LF stoichiometry under which Lactoferrin (LF) and B-lactoglobulin (BLG) form optically clear coacervates. These constraints on conditions for pure coacervation were also attributed to the requirements for the formation of a basic primary unit, LF(BLG)4 , characterized in the supernatant and coacervate. Coacervate is characterized as a solidlike transient network of primary units embedded into a viscoelastic suspending fluid.

This dissertation explores the design, synthesis, and structure of aromatic molecules with the goal of understanding the forces which affect packing of conjugated molecules in the solid state. Two approaches were applied to direct the assembly of aromatic materials. The first one involved the use of coordination bonds between aromatic nitriles and silver(I) triflate. Several acridine-based ligands were synthesized and crystallized, alone and complexed to silver(I) triflate. Generally, ligands that possessed three peripheral coordination sites formed sheet-like crystal structures. Ligands with only one coordination site crystallized into columnar arrangements with significant edge-to-face interactions. The second approach studied the effect of mutually phobic side-chains on the properties of dyads - molecules comprised of linked electron-rich and electron-poor aromatic moieties. It was shown that, despite attractive electrostatic forces between electron-rich and electron-poor aromatic species, aliphatic hydrocarbon and fluorocarbon side-chains form segregated domains in single crystals. Finally, the mutually phobic side-chain approach was extended to materials based on oligo- or poly-thiophene and naphthalenediimide.

Materials with nanoscale dimensions display electronic, photonic, and magnetic properties different from those observed by their respective bulk materials. This thesis work has focused on the utilization of molecular recognition for modular self-assembly of nano-sized building blocks into two or three-dimensional aggregates and the precise control over their structural parameters and morphologies. Special attention will be given to the design and synthesis of molecular and macromolecular building blocks to generate micron and nanometer-scale order, to tailor local surface properties through site-selective immobilization, and to create responsive/adaptive functional materials in a controlled, reproducible, and reversible manner. The advantages, potential applications, and current challenges associated with this "bottom up" self-assembly approach will also be discussed. I am going to demonstrate in the following chapters how we synthesized functionalized Au and CdSe nanoparticles (NPs), styrene based block copolymer with pended recognition units, and diamidopyridine ( DAP)—thymine (Thy) three-point hydrogen bonding dyads that induced recognition-mediated self-assembly of polymers and NPs into ordered and tunable/responsive nanocomposites. The resultant composite materials were addressed onto photo-lithographically defined surface regions. Desired electrical conductivity, surface wettability and biocompatibility were achieved by choosing appropriate polymers and NPs—the versatile building blocks for nanocomposite functional materials.

The development of highly selective and very sensitive methods to detect peptides and proteins of interest in complex mixtures remains an important goal in proteomics applications. This dissertation focuses on the use of reverse-micelle forming amphiphilic homopolymers as part of liquid-liquid extraction to selectively extract and concentrate peptides from an aqueous solution into an immiscible organic phase. After extraction, the polymer-peptide mixtures are amenable to direct analysis by matrix assisted laser desorption ionization mass spectrometry (MALDI-MS). The charged interiors of the reverse micelles enable oppositely charged peptides to be selectively extracted into the aggregate’s cores via coulombic attraction. Reverse micelles formed by negatively charged carboxylic acid or positively charged quaternary amine groups can be used alone or in sequence to selectively extract and fractionate peptides according to their isoelectric points (pIs). Furthermore, the pI cutoff can be readily tuned by adjusting the extraction pH. The coalescence of polymer-peptide conjugates into hotspots on the MALDI target plate during MALDI-MS analysis results in significant signal enhancement for the enriched peptides, enabling reproducible ion signals at concentrations as low as 10 fM. Interestingly, reverse micelles formed by positively charged polymers with quaternary amine substituents can selectively enrich acidic peptides that are undetectable during regular MALDI-MS analysis. The extraction protocol along with MALDI-MS can also be used for the selective enrichment and detection of low abundance peptide/protein biomarkers in human serum at physiologically relevant concentrations. Overall, the results described in this dissertation reveal that this selective extraction protocol along with MALDI-MS analysis might have a significant impact on protein identification and early stage screening of biomarkers.

The applications of stimuli responsive materials have tremendously increased over the past decade. In particular, these materials can potentially be used for improving the selectivity and efficiency of delivering a payload (drug) in drug delivery applications. This thesis discusses the design and synthesis of amphiphilic polymers which can respond to chemical, physical, and biological stimuli. We have synthesized a novel amphiphilic block copolymer which can form micellar assemblies in aqueous medium and respond to multiple stimuli; viz physical (temperarure) and chemical (pH, DTT and gluthathione). This amphiphilic block copolymer is sensitive not only to a single stimulus, but also to the simultaneous presence of multiple stimuli. This system provides a unique opportunity to fine tune the release kinetics of the encapsulated hydrophobic guest molecules. Besides designing polymeric systems responsive to chemical and physical stimuli, we were also interested in systems responsive to biological stimuli, since they can directly respond to the primary imbalances in biological functions instead of a secondary change such as pH, or redox potential characteristics. Amphiphilic polymers designed earlier in the group with –COOH as the hydrophilic group are known to provide micellar assemblies in water. The charged exterior (-COO-) of the micellar assemblies was used to disrupt protein-protein interaction. To further investigate if these polymeric micelles can be made responsive to proteins, we have studied the binding event of a ligand (pendant on the polymer chain) with the protein. Block copolymers and random copolymers functionalized with specific ligands were used as model systems to understand the interaction of polymers with proteins. We established that block copolymers provide better binding with proteins compared to random copolymers, possibly due to the higher effective molarity of ligands present in the former than the latter. Amphiphilic biaryl dendrimers decorated with ligands at different locations were also studied. We established that ligands present in at any layer of the dendron are equally available for binding with protein. Amphiphilic homopolymer and amphiphilic biaryl dendrimer were found to be the potential candidates for drug delivery applications by using proteins as the trigger to disassemble the micelles.

Dendrimers, due to their well-controlled size and shape, have emerged as interesting macromolecular scaffolds for fundamental applications in materials to medicine. Amphiphilic dendrimers are among the attractive molecular systems for applications in drug delivery due to their ability to solubilize hydrophobic guest molecules in water. This thesis focuses on a class of amphiphilic biaryl dendrimers that self-assembles to form solvent-dependant supramolecular assemblies, and discusses the following: (i) Molecular design and synthetic strategies for incorporating a single probe unit at specific locations of the dendrimer backbone for understanding microenvironment variation in dendrimer molecules. (ii) Study on the self-assembling properties of amphiphilic dendrimers that are functionalized with bioactive moieties. (iii) Demonstration of the disassembly of the amphiphilic assemblies of these dendrimers using both enzymatic and non-enzymatic proteins. It also elaborates the disassembly-driven release of hydrophobic guest molecules from the assembly interiors. The findings of this dissertation would provide molecular level understanding on both self-assembling properties of amphiphilic macromolecules and strategies to disassemble the amphiphilic assemblies using biological triggers such as proteins.

Recent progress in nanotechnology research has witnessed its impact in wide variety of emerging fields starting from electronics to medicine. Our interest in nanotechnology is to ‘create new nanomaterials’, or ‘new methods to make nanomaterials’, to understand and to utilize them for various applications. We discuss our findings on the formation and application of nanostructures made through self-assembly in solution, followed by self-assembly at the interior of nanopores. Self-assembly can be induced in molecules by manipulating the noncovalent interaction, solvophilic and solvophobic forces. We are interested in creating various selfassembled nanostructures that could be tuned by modifying the amphiphilic building blocks during their synthesis. When these building blocks are grown in a perfectly branched fashion the obtained macromolecules are called amphiphilic dendrimers, whereas the linearly grown building blocks are called amphiphlic homopolymers. Here we show that the biaryl dendrimer can be made into temperature sensitive micelles, and can be used in molecular encapsulation. We further extend our developed concept to acrylamide-based homopolymers that can, not only form micelles and inverted micelles, but also can be tuned to make vesicles. By making the amphiphilic homopolymer in a noncovalent fashion, we show that the formed nanoassembly can be disassembled using proteins and the differential nature of disassembly was used for protein sensing. The self-assembled structures in apolar solvent, known as inverted micelles, were utilized for pI-dependent isolation of peptides. We show that polymers can be self-assembled inside membrane nanopores to make functionalized nanotubes, which can be utilized for separating molecules based on charge, size and hydrophobicity. We also show that by using dendrimers the pore size of the nanotubes can be precisely controlled and can be exploited for molecular separations.

The synthesis and physical characterization of various poly(1,4-phenylene vinylene) (PPVs) derivatives with electron withdrawing substituents on the phenyl rings and some additional PPV analogues are described. The synthetic routes used were a variation on the Wessling route to PPV which involves a processible precursor polymer. All polymers were characterized by IR, UV and elemental analysis. The effect of substitution on the phenyl ring and solvent effects on polymerization were also discussed. Para-xylylenes were generated by treatment of various 1,4-bis(dialkylsulfoniomethyl) arene dihalides in different solvents and detected by UV-VIS spectroscopy. The utility of studying the UV-VIS spectral behavior of para-xylylenes and analogues in the Wessling polyelectrolyte precursor process for synthesis of poly(arylene vinylene)s is demonstrated by several examples. Electronic spectral properties such as UV-VIS absorption and photoluminescence spectroscopy of PPV derivatives and analogues were investigated.